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Manufacturers: Abbott Laboratories (USA)
Active ingredients
- Paricalcitol
Disease class
- Secondary hyperparathyroidism, not elsewhere classified
- Help including dialysis
- Chronic renal failure
- End stage kidney disease
Clinical and pharmacological group
- Not indicated. See instructions
Pharmacological action
- Not indicated. See instructions
Pharmacological group
- Correctors of bone and cartilage tissue metabolism
Zemplar injection solution
Instructions for medical use of the drug
Description of pharmacological action
Paricalcitol is a synthetic analogue of biologically active vitamin D (calcitriol), the structure of which contains modifications of the side chain (D2) and ring A (19-nor), which determine the tissue and organ selectivity of paricalcitol. Paricalcitol selectively activates vitamin D receptors (PBD) in the parathyroid glands without increasing PBD activity in the intestine and has a less potent effect on bone resorption. Paricalcitol also activates calcium-sensing receptors in the parathyroid glands, thereby reducing PTH levels by inhibiting parathyroid proliferation and reducing PTH synthesis and secretion. Has minimal effects on calcium and phosphorus levels and may directly affect bone cells. By correcting pathological levels of PTH and normalizing calcium and phosphorus homeostasis, it can prevent and treat bone diseases associated with impaired metabolism due to chronic kidney disease. Secondary hyperparathyroidism is characterized by an increase in PTH levels, which is associated with inadequate levels of active vitamin D. This vitamin is synthesized in the skin and enters the body with food. Vitamin D is sequentially hydroxylated in the liver and kidneys and converted into an active form that interacts with vitamin D receptors. The active form of vitamin D - 1,25(OH)2 D3 - activates vitamin D receptors in the parathyroid glands, intestines, kidneys and bone tissue ( due to this, it supports parathyroid function and calcium and phosphorus homeostasis), as well as in many other tissues, including the prostate, endothelium and immune cells. Activation of the receptors is necessary for adequate bone formation. In kidney disease, the activation of vitamin D is suppressed, which leads to an increase in PTH levels, the development of secondary hyperparathyroidism and disruption of calcium and phosphorus homeostasis. A decrease in 1,25(OH)2D3 levels was observed in the early stages of chronic kidney disease. Decreased 1,25(OH)2D3 levels and increased PTH activity, which often precede changes in serum calcium and phosphorus levels, cause changes in bone turnover and may lead to the development of renal osteodystrophy. In patients with chronic kidney disease, a decrease in PTH levels has a beneficial effect on bone alkaline phosphatase activity, bone turnover, and bone fibrosis. At the same time, therapy with active vitamin D can lead to increased levels of calcium and phosphorus. Paricalcitol, due to its selective effect on vitamin D receptors, effectively reduces PTH levels, normalizes bone metabolism, and allows one to prevent and eliminate the consequences of insufficient activation of vitamin D receptors without significantly affecting the level of calcium and phosphorus.
Indications for use
Prevention and treatment of secondary hyperparathyroidism that develops in chronic kidney disease stages 3 and 4, as well as in patients with stage 5 chronic kidney disease who are on hemodialysis or peritoneal dialysis.
Release form
solution for intravenous administration 5 mcg/ml; ampoule 1 ml, cardboard pack 5; solution for intravenous administration 5 mcg/ml; ampoule 1 ml, contour plastic packaging (pallets) 5, cardboard pack 1; solution for intravenous administration 5 mcg/ml; ampoule 2 ml, cardboard pack 5; solution for intravenous administration 5 mcg/ml; ampoule 2 ml, contour plastic packaging (pallets) 5, cardboard pack 1; solution for intravenous administration 5 mcg/ml; ampoule 1 ml, cardboard pack 5; solution for intravenous administration 5 mcg/ml; ampoule 1 ml, contour plastic packaging (pallets) 5, cardboard pack 1; Composition Solution for intravenous administration 1 ml paricalcitol 5 mcg excipients: ethanol (95%) - 20%, propylene glycol - 30%, water for injection - up to 1 ml in 1 ml ampoules; in a cardboard pack of 5 ampoules or in a blister pack (pallet) 5 ampoules; in a cardboard pack 1 package (pallet).
Pharmacodynamics
Paricalcitol is a synthetic analogue of biologically active vitamin D (calcitriol), the structure of which contains modifications of the side chain (D2) and ring A (19-nor), which determine the tissue and organ selectivity of paricalcitol. Paricalcitol selectively activates vitamin D receptors (PBD) in the parathyroid glands without increasing PBD activity in the intestine and has a less potent effect on bone resorption. Paricalcitol also activates calcium-sensing receptors in the parathyroid glands, thereby reducing PTH levels by inhibiting parathyroid proliferation and reducing PTH synthesis and secretion. Has minimal effects on calcium and phosphorus levels and may directly affect bone cells. By correcting pathological levels of PTH and normalizing calcium and phosphorus homeostasis, it can prevent and treat bone diseases associated with impaired metabolism due to chronic kidney disease. Secondary hyperparathyroidism is characterized by an increase in PTH levels, which is associated with inadequate levels of active vitamin D. This vitamin is synthesized in the skin and enters the body with food. Vitamin D is sequentially hydroxylated in the liver and kidneys and converted into an active form that interacts with vitamin D receptors. The active form of vitamin D - 1,25(OH)2 D3 - activates vitamin D receptors in the parathyroid glands, intestines, kidneys and bone tissue ( due to this, it supports parathyroid function and calcium and phosphorus homeostasis), as well as in many other tissues, including the prostate, endothelium and immune cells. Activation of the receptors is necessary for adequate bone formation. In kidney disease, the activation of vitamin D is suppressed, which leads to an increase in PTH levels, the development of secondary hyperparathyroidism and disruption of calcium and phosphorus homeostasis. A decrease in 1,25(OH)2D3 levels was observed in the early stages of chronic kidney disease. Decreased 1,25(OH)2D3 levels and increased PTH activity, which often precede changes in serum calcium and phosphorus levels, cause changes in bone turnover and may lead to the development of renal osteodystrophy. In patients with chronic kidney disease, a decrease in PTH levels has a beneficial effect on bone alkaline phosphatase activity, bone turnover, and bone fibrosis. At the same time, therapy with active vitamin D can lead to increased levels of calcium and phosphorus. Paricalcitol, due to its selective effect on vitamin D receptors, effectively reduces PTH levels, normalizes bone metabolism, and allows one to prevent and eliminate the consequences of insufficient activation of vitamin D receptors without significantly affecting the level of calcium and phosphorus.
Pharmacokinetics
Within 2 hours after administration of paricalcitol intravenously in the form of a bolus in doses of 0.04 to 0.24 mcg/kg, the concentration of the drug decreases rapidly; however, subsequently the concentration of the drug decreases linearly, with an average T1/2 of about 15 hours. With repeated use of paricalcitol, no signs of cumulation are observed. Distribution. Paricalcitol is actively bound to plasma proteins (>99%). In healthy people, the volume of distribution at steady state is about 23.8 L. In patients with stage 5 chronic kidney disease treated with hemodialysis or peritoneal dialysis, the volume of distribution of paricalcitol at a dose of 0.24 mcg/kg averages 31–35 L. The pharmacokinetics of paricalcitol was studied in patients with chronic renal failure treated with hemodialysis. Metabolism. Several metabolites of the drug are detected in urine and feces. Unchanged paricalcitol was not detected in urine. Paricalcitol is metabolized by numerous hepatic and non-hepatic enzymes, including mitochondrial CYP24, as well as CYP3A4 and UGT1A4. Identified metabolites include products of 24(R)-hydroxylation (found in low concentrations in plasma), as well as 24,26- and 24,28-dihydroxylation and direct glucuronidation. Paricalcitol does not have an inhibitory effect on CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A at concentrations up to 50 nM (21 ng/ml). At similar concentrations of paricalcitol, the activity of CYP2B6, CYP2C9 and CYP3A4 increases by less than 2 times. Excretion. Paricalcitol is eliminated by excretion in bile. In healthy people, approximately 63% of the drug is excreted through the intestines and 19% through the kidneys. T1/2 of paricalcitol in doses from 0.04 to 0.16 mcg/kg in healthy volunteers averages 5–7 hours. Special groups Elderly people. The pharmacokinetics of paricalcitol in people over 65 years of age have not been studied. Children. The pharmacokinetics of paricalcitol in children and adolescents less than 18 years of age have not been studied. Floor. The pharmacokinetics of paricalcitol does not depend on gender. Liver dysfunction. The pharmacokinetics of paricalcitol (at a dose of 0.24 mcg/kg) was compared in patients with mild to moderate hepatic impairment (Child-Pugh classification) and healthy subjects. The pharmacokinetics of unbound paricalcitol were similar in these patient groups. No dose adjustment is required in patients with mild or moderate liver dysfunction. The pharmacokinetics of paricalcitol in patients with severe hepatic impairment has not been studied. Renal dysfunction. The pharmacokinetics of paricalcitol was studied in patients with stage 5 chronic kidney disease treated with hemodialysis or peritoneal dialysis. Hemodialysis did not have a significant effect on the excretion of paricalcitol. However, in patients with stage 5 chronic kidney disease, a decrease in clearance and an increase in T1/2 were found compared to healthy people.
Use during pregnancy
No studies have been conducted in pregnant women. There is no information on the excretion of paricalcitol in breast milk in women. Paricalcitol can be used during pregnancy only if the potential benefit to the mother justifies the possible risk to the fetus. If it is necessary to use the drug during lactation, breastfeeding should be stopped.
Contraindications for use
- hypersensitivity to any component of the drug; — hypervitaminosis D; - combined use with phosphates or vitamin D derivatives; - hypercalcemia; - children under 18 years of age (clinical studies have not been conducted); - period of breastfeeding. With caution: combined use with cardiac glycosides.
Side effects
Among the side effects in patients with stage 3 and 4 chronic kidney disease treated with paricalcitol, the most common side effects were skin rashes (in 2% of patients). All adverse events, both clinical and laboratory, the connection of which with the use of paricalcitol could be characterized as at least possible, are presented by organ system and frequency of development. According to the frequency of development, they are divided into the following groups: very often (≥1/10), often (≥1/100, Adverse reactions in patients with chronic kidney disease stages 3 and 4, described in clinical studies From the central nervous system: infrequently - dizziness. From the digestive system: infrequently - taste disturbance, constipation, dry mouth, dyspepsia, gastritis, abnormal liver test results. From the skin: often - skin rash; infrequently itching, urticaria. From the musculoskeletal system: Uncommon: muscle cramps of the lower extremities. Other: Uncommon: allergic reactions. Adverse reactions in patients with stage 5 chronic kidney disease, described in a phase III clinical study. From the digestive system: often: anorexia, diarrhea, gastrointestinal disorders. From the central nervous system. : often - dizziness. From the skin: often - acne. Others: often - breast pain, hypercalcemia, hypocalcemia. Adverse reactions recorded during post-marketing observations: Quincke's edema and laryngeal edema.
Overdose
An overdose of paricalcitol can lead to the development of hypercalcemia, hypercalciuria, hyperphosphatemia and suppression of PTH secretion. Acute overdose of paricalcitol can lead to the development of hypercalcemia and requires emergency care. During dose selection, serum calcium and phosphorus levels should be regularly monitored. Long-term therapy with paricalcitol may be complicated by hypercalcemia, increased Ca × P and soft tissue calcification (metastatic calcification). If clinically significant hypercalcemia occurs, the dose of paricalcitol should be immediately reduced or treatment interrupted. Recommended measures include a hypocalcium diet, discontinuation of calcium supplements, monitoring of fluid and electrolyte balance, assessment of electrocardiographic changes (critical for patients receiving cardiac glycosides) and hemodialysis or peritoneal dialysis using a calcium-free dialysate. Serum calcium levels should be monitored regularly until they return to normal. When PTH levels are suppressed below normal, adynamic bone disease, a pathological condition with low bone turnover, may develop.
Interactions with other drugs
In accordance with in vitro studies, paricalcitol should not inhibit the clearance of drugs that are metabolized by CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A cytochrome P450 isoenzymes, or induce the clearance of substances biotransformed by CYP2B6, CYP2C9 or CYP3A. The interaction of paricalcitol injection with other drugs has not been specifically studied. When studying the interaction of ketoconazole and paricalcitol in capsules, it was shown that ketoconazole causes an approximately 2-fold increase in the AUC0–∞ of paricalcitol. Paricalcitol is partially metabolized by CYP3A, and ketoconazole is a potent inhibitor of cytochrome P450 3A, so caution should be exercised when combining paricalcitol with ketoconazole and other potent P450 3A inhibitors. Hypercalcemia of any nature increases intoxication with cardiac glycosides, so caution must be exercised when using them in combination with paricalcitol.
Special instructions for use
Excessive suppression of PTH secretion can lead to increased serum calcium levels and decreased bone turnover. To achieve physiological parameters, monitoring the patient’s condition and individual dose selection are necessary. If clinically significant hypercalcemia develops in a patient taking calcium-containing phosphate binders, the dose of the latter should be reduced or its use interrupted. During initial dose adjustment or any dose change, serum calcium, phosphorus, serum phosphorus, or plasma iPTH levels should be determined at least every 2 weeks for 3 months after initiation of treatment with paricalcitol capsules or after a dose change of paricalcitol, then monthly thereafter. 3 months, then every 3 months. There were no differences in efficacy or safety in patients aged 65 years and older. Use in pediatrics The effectiveness and safety of paricalcitol in children has not been studied.
Storage conditions
At a temperature of 15–25 °C (do not freeze).
Best before date
24 months
Zemplar®
Within two hours after administration of paricalcitol intravenously as a bolus in doses of 0.04 to 0.24 mcg/kg, the concentration of paricalcitol decreases rapidly; however, paricalcitol concentrations subsequently decrease linearly, with an average half-life of approximately 15 hours. With repeated use of paricalcitol, no signs of accumulation are observed.
Distribution
Pari calcitol is actively bound to plasma proteins (>99%). In healthy people, the volume of distribution at steady state is about 23.8 L. In patients with stage 5 chronic kidney disease (end-stage renal failure - creatinine clearance less than 15 ml/min/1.73 m2 or the need for continuous dialysis) treated with hemodialysis or peritoneal dialysis, the volume of distribution of paricalcitol at a dose of 0.24 mcg/kg is on average 31-35 l. The pharmacokinetics of paricalcitol was studied in patients with chronic renal failure treated with hemodialysis.
Metabolism
Several metabolites of paricalcitol are detected in urine and feces. Unchanged paricalcitol was not detected in urine. Paricalcitol is metabolized by numerous hepatic and extrahepatic enzymes, including the mitochondrial isoenzyme CYP24, as well as the CYP3A4 and UGT1A4 isoenzymes. Identified metabolites include products of 24(R)-hydroxylation (found in low concentrations in plasma), as well as 24,26- and 24,28-dihydroxylation and direct glucuronidation. Paricalcitol does not have an inhibitory effect on the isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A at concentrations up to 50 nmol/l (21 ng/ml). At similar concentrations of paricalcitol, the activity of the isoenzymes CYP2B6, CYP2C9 and CYP3A4 increases by less than 2 times.
Removal
Paricalcitol is eliminated by excretion in bile. In healthy people, approximately 63% of paricalcitol is excreted through the intestines and 19% through the kidneys. The half-life (T1/2) of paricalcitol in doses from 0.04 to 0.16 mcg/kg in healthy volunteers averages 5-7 hours.
Liver dysfunction
The pharmacokinetics of paricalcitol (0.24 mcg/kg) were compared in patients with mild to moderate hepatic impairment (Child-Pugh classes A and B) and healthy subjects. The pharmacokinetics of unbound paricalcitol were similar in these patient groups.
No dose adjustment is required in patients with mild or moderate liver dysfunction. The pharmacokinetics of parcal citol have not been studied in patients with severe hepatic impairment.
Renal dysfunction
The pharmacokinetics of paricalcitol was studied in patients with stage 5 chronic kidney disease treated with hemodialysis or peritoneal dialysis. Hemodialysis did not have a significant effect on the excretion of paricalcitol. However, in patients with stage 5 chronic kidney disease, a decrease in clearance (Cl) and an increase in T1/2 of paricalcitol were found compared to healthy people.
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